Bisacodyl, 4,4'-(2-pyridylmethylene)bisphenoldiacetate, is disclosed in the Merck Index, 11th ed. (1989), S. Budavari, ed., No. 1253, p. 193. Bisacodyl is an inactive prodrug that is hydrolyzed by intestinal brush border enzymes and colonic bacteria to desacetyl bisacodyl which is the active species. (R. Jauch, R. Hankwitz, K. Beschke, & H. Pelzer, "Bis-(p-hydroxyphenyl)-pyridyl-2-methane: The Common Laxative Principle of Bisacodyl and Sodium Picosulfate", Arzneim.-Forsch./Drug Res. 25 (11), 1796-1800, 1975). Contact of the desacetyl bisacodyl with the mucosa of the colon stimulates sensory nerve endings to produce increased propulsive peristaltic contractions of the colon which accelerate movement of contents through the colon. Both bisacodyl and desacetyl bisacodyl are poorly water soluble with absorption reported from both the small intestine and colon. Absorption from the small intestine may be greater than from the colon.
Delivery of suspensions or solutions of bisacodyl to the colon is known to result in laxation. (M. A. Kamm, J. E. Lennard-Jones, D. G. Thompson, R. Sobnack, N. W. Garvie, N, Granowska, "Dynamic Scanning Defines a Colonic Defect in Severe Idiopathic Constipation", Gut, Vol. 29, pp 1085-1092, 1988; D. M. Preston, J. E. Lennard-Jones, "Pelvic Motility and Response to Intraluminal Bisacodyl in Slow-Transit Constipation", Digestive Diseases and Sciences, Vol. 30, No 4, pp 289-294, 1985; E. Leng-Peschlow,"Effect of Sennosides A+B and Bisacodyl on Rat Large Intestine", Pharmacology, Vol. 38, pp 310-318, 1988).
A dosage form that truly delivers a concentrated form of bisacodyl to the colon, with minimum absorption occurring in the small intestine, would be desirable for several reasons. Since desacetyl bisacodyl acts upon contact with the lumenal mucosa of the colon, its laxative effect is dependent upon generation of sufficient levels of the drug in the lumen of the colon. However, it has been determined that secondary diarrhea and/or repeat bowel movements associated with peroral administration of bisacodyl is at least partially due to the fact that absorbed desacetyl bisacodyl is partially excreted in the bile as the glucuronide conjugate which can be subsequently cleaved by colonic bacteria releasing desacetyl bisacodyl. Therefore, it is desirable to minimize absorption of desacetyl bisacodyl from the small intestine and colon while achieving therapeutically effective levels of the drug in the lumen of the colon. Lower doses of bisacodyl can be used if bisacodyl is delivered in an undiluted, rapidly dissolving form, to its site of activity in the colon. Low doses will provide laxation efficacy with minimal side effects such as repeat bowel movements, cramping, and secondary diarrhea.
Release of bisacodyl in the colon as a preferred mode of delivery of the drug in order to minimize systemic absorption of bisacodyl is disclosed in W. Roth, K. Beschke, "Pharmacokinetics and Laxative Effect of Bisacodyl after Administration of Various Dosage Forms", Arzneim.-Forsch./Drug Res., Vol. 38(I), No. 4 (1988), pp. 570-574.
Commercially-available bisacodyl compositions are typically coated with a low level of an enteric polymer or combination of polymers. An example of such a commercially available product is Dulcolax.RTM. (Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn.). (See also, enteric coated bisacodyl tablets indicated for the relief of constipation in the Physician's Desk Reference for Non Prescription Drugs, 13th ed. (1992), p. 550.) Dulcolax.RTM. is typically coated with a low level of cellulose acetate phthalate, and each tablet has about 5 mg of bisacodyl. The recommended dose is from 1 to 3 tablets (from 5 to 15 mg of bisacodyl). Another example is Colac.RTM. (Procter & Gamble Pharmaceuticals) which is coated with a low level of a 50/50 mixture of Eudragit.RTM.S and Eudragit.RTM.L, with the same recommended dosing as Ducolox.RTM.. These bisacodyl formulations are formulated in such a way that they are not rapidly dissolving once the bisacodyl reaches the colon. In addition the level of coating is much less than the amount required by the present invention.
Colonic delivery dosage forms are known in the art. For example, U.S. Pat. No. 5,171,580, issued Dec. 15, 1992, Boehringer Ingelheim Italia, teaches a preparation for delivery in the large intestine and especially the colon, comprising an active containing core coated with three protection layers of coatings having different solubilities. The inner layer is Eudragit.RTM.S, with a coating thickness of about 40-120 microns, the intermediate coating layer is a swellable polymer with a coating thickness of about 40-120 microns, and the outer layer is cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl cellulose phthalate, cellulose acetate tetrahydrophthalate, or Eudragit.RTM.L. In the dosage forms of the present invention Eudragit.RTM.S is only used as an outer layer.
U.S. Pat. No. 4,910,021, issued on Mar. 20, 1990, Scherer Corp., teaches a targeted delivery system wherein the composition comprises a hard or soft gelatin capsule containing an active ingredient such as insulin and an absorption promoter, which is coated with a film forming composition being sufficiently soluble at a pH above 7 as to be capable of permitting the erosion or dissolution of said capsule. The film forming composition is preferably a mixture of Eudragit.RTM.L, Eudragit.RTM. RS, and Eudragit.RTM. S at specific ratios to provide solubility above a pH of 7.
U.S. Pat. No. 4,432,966, issued on Feb. 21, 1984, Roussel-UCLAF, teaches a compressed tablet with an active agent, coated with a first coating layer comprising a mixture of microcrystalline cellulose and lower alkyl ether of a cellulose film-forming organic polymer such as ethyl cellulose, and a second coating layer selected from cellulose acetylphthalate, hydroxypropyl methylcellulose phthalate, benzophenyl salicylate, cellulose acetosuccinate, copolymers of styrene and of maleic acid, formulated gelatin, salol, keratin, steraric acid, myristic acid, gluten, acrylic and methacrylic resins, and copolymers of maleic acid and phthalic acid derivatives.
In addition, the art also teaches that certain coating compositions are advantageous for ease of processing. For example, U.S. Pat. No. 5,330,759, issued Jul. 19, 1994, Sterling Winthrop, Inc., teaches soft capsules coated with an enteric coating comprising from about 1 to about 20 mg./cm.sup.2 of 1:1 copolymer of methacrylic acid and methyl or ethyl acrylate or methyl ethyl methacrylate and a plasticizer. Gildants such as talc, to prevent agglomeration of the capsules, and a subcoating, to stiffen the capsules and thereby prevent distortion during coating, are not needed. This reference does not teach colonic delivery nor the importance of a smooth substrate surface without edges or sharp curves, and does not teach the specific multiple coating layers required by the present invention.
In addition, dosage forms with higher levels of coating are also known in the art. For example U.S. Pat. No. 5,068,110, issued on Nov. 26, 1991, Warner-Lambert Co., teaches dosage forms with a high level of enteric coating using aqueous systems in their manufacturer, such as Eudragit.RTM. L30D, Aquateric.RTM. (cellulose acetate phthalate) and Coateric.RTM. (polyvinyl acetate phthalate), for improved dissolution stability for storage under high stress conditions. The coating levels disclosed are from 14 mg/cm.sup.2 to 24 mg/cm.sup.2, of a single layer of one enteric polymer. These dosage forms are delivered to the small intestine as opposed to the colon.
In summary, colonic delivery of a peroral unit dosage form from which bisacodyl rapidly dissolves in the colon, will provide a higher in-situ concentration of the active compound for a more localized effect, permitting the use of lower doses, resulting in lower side effects. Therefore, a peroral dosage form which will preserve bisacodyl throughout the upper part of the gastrointestinal tract and thereafter rapidly release it in the colon, is desirable.
It is an object of the present invention to provide a dosage form of bisacodyl which provides laxation efficacy to patients without the occurrence of significant side effects such as substantial secondary diarrhea, repeat bowel movements and cramping.
It is a further object of the present invention to provide laxation efficacy at substantially lower doses than is required with current peroral dosage forms of bisacodyl.